Many diseases of the central nervous system are influenced by the adrenergic, the dopaminergic, and the serotonergic neurotransmitter systems. For example, serotonin has been implicated in a number of diseases and conditions which originate in the central nervous system. A number of pharmacological and genetic experiments involving receptors for serotonin strongly implicate the 5-HT2c receptor subtype in the regulation of food intake (Obes. Res. 1995, 3, Suppl. 4, 449S-462S). The 5-HT2c receptor subtype is transcribed and expressed in hypothalamic structures associated with appetite regulation. It has been demonstrated that the non-specific 5-HT2c receptor agonist m-chlorophenylpiperazine (mCPP), which has some preference for the 5-HT2c receptor, causes weight loss in mice that express the normal 5-HT2c receptor while the compound lacks activity in mice expressing the mutated inactive form of the 5-HT2c receptor (Nature 1995, 374, 542-546). In a recent clinical study, a slight but sustained reduction in body weight was obtained after 2 weeks of treatment with mCPP in obese subjects (Psychopharmacology 1997, 133, 309-312). Weight reduction has also been reported from clinical studies with other “serotonergic” agents (see e.g. IDrugs 1998, 1, 456-470). For example, the 5-HT reuptake inhibitor fluoxetine and the 5-HT releasing agent/reuptake inhibitor dexfenfluramine have exhibited weight reduction in controlled studies. However, currently available drugs that increase serotonergic transmission appear to have only a moderate and, in some cases, transient effects on the body weight.
The 5-HT2c receptor subtype has also been suggested to be involved in CNS disorders such as depression and anxiety (Exp. Opin. Invest. Drugs 1998, 7, 1587-1599; IDrugs, 1999, 2, 109-120).
The 5-HT2c receptor subtype has further been suggested to be involved in urinary disorders such as urinary incontinence (IDrugs. 1999, 2, 109-120).
Compounds which have a selective effect on the 5-HT2c receptor may therefore have a therapeutic potential in the treatment of disorders like those mentioned above. Of course, selectivity also reduces the potential for adverse effects mediated by other serotonin receptors.
Information disclosure
U.S. Pat. No. 3,253,989 discloses the use of mCPP as an anorectic agent.
EP-A 1-863 136 discloses azetidine and pyrrolidine derivatives which are selective 5-HT2c receptor agonists having antidepressant activity and which can be used for treating or preventing serotonin-related diseases, including eating disorders and anxiety.
EP-A-657 426 discloses tricyclic pyrrole derivatives having activity on the 5-HT2c receptor and which inter alia may be used for treating eating disorders.
EP-A-655 440 discloses 1-aminoethylindoles having activity on the 5-HT2c receptor and which may be used for treating eating disorders.
EP-A-572 863 discloses pyrazinoindoles having activity on the 5-HT2c receptor and which may be used for treating eating disorders.
J. Med. Chem. 1978, 21, 536-542 and U.S. Pat. No. 4,081,542 disclose a series of piperazinylpyrazines having central serotonin-mimetic activity.
J. Med. Chem. 1981, 24, 93-101 discloses a series of piperazinylquinoxalines with central serotoninmimetic activity.
WO 00/12475 discloses indoline derivatives as 5-HT2b and/or 5-HT2c receptor ligands, especially for the treatment of obesity.
WO 00/12510 discloses pyrroloindoles, pyridoindoles and azepinoindoles as 5-HT2c receptor agonists, particularly for the treatment of obesity.
WO 00/12482 discloses indazole derivatives as selective, directly active 5-HT2c receptor ligands, preferably 5-HT2c receptor agonists, particularly for use as anti-obesity agents.
WO 00/12502 discloses pyrroloquinolines as 5-HT2c receptor agonists particularly for use as anti-obesity agents.
WO 00/12475 discloses indoline derivatives as 5-HT2b and/or 5-HT2c receptor ligands, especially for the treatment of obesity.
GB-B-1,457,005 discloses 1-piperazinyl-2-[2-(phenyl)ethenyl]-quinoxaline derivatives which exhibit anti-inflammatory activity.
Chem. Pharm. Bull. 1993, 41(10) 1832-1841 discloses 5-HT3 antagonists including 2-(4-methyl-1-piperazinyl)-4-phenoxyquinoxaline.
GB-B-1,440,722 discloses 2-(1′-piperazinyl)-quinoxaline compounds having pharmaceutical activity against depression.
WO 96/11920 discloses CNS-active pyridinylurea derivatives.
WO 95/01976 discloses indoline derivatives active as 5-HT2c antagonists and of potential use in the treatment of CNS disorders.
WO 97/14689 discloses aryl-piperazine cyclic amine derivatives which are selective 5-HT1d receptor antagonists.
WO 98/42692 discloses piperazines derived from cyclic amines which are selective antagonists of human 5-HT1a, 5-HT1d and 5-HT1b receptors.
GB-B-1,465,946 discloses substituted pyridazinyl, pyrimidinyl and pyridyl compounds which are active as β-receptor blocking agents.
EP-A-711757 discloses [3-(4-phenyl-piperazin-1-yl)propylamino]-pyridine, pyrimidine and benzene derivatives as α-adrenoceptor antagonists.
WO 99/03833 discloses aryl-piperazine derivatives which are 5-HT2 antagonists and 5-HT1a receptor agonists and therefore are useful as remedies or preventives for psychoneurosis.
WO 96/02525 discloses aryl-piperazine-derived piperazide derivatives having 5-HT receptor antagonistic activity.
WO 99/58490 disloses aryl-hydronaphthalen-alkanamines which may effectuate partial or complete blockage of serotonergic 5-HT2c receptors in an organism.